Device for medicine delivery by intraocular iontophoresis or electroporation

ABSTRACT

The invention concerns a device for ocular delivery of an active principle by peroperative intraocular iontophoresis or electroporation comprising a reservoir ( 7 ) for receiving a solution comprising the active principle, means for diffusing ( 8, 6 ) the active principle connected to the reservoir, means for injecting ( 4 ) the solution into the reservoir, and means ( 5 ) for exerting suction of the content of the reservoir during an injection of the solution therein by the injection means.

The invention relates to a device for applying an active principle byiontophoresis or electroporation, intended for eye treatment so as toimprove the intraocular delivery of active principles in ophthalmology.

Iontophoresis, like electroporation, uses electric current to allow thediffusion of a charged molecule through a biological membrane. Thepermeability of the biological membrane is increased under the effect ofthe electric current, thereby allowing the passage of larger molecules,and the electric field pushes the molecules through this membrane.

At present, existing ocular iontophoresis devices are perioculardevices. The document U.S. Pat. No. 4,564,016 discloses such a devicewhich comprises a balloon mounted on the distal end of a probe. Thisballoon makes it possible to clear the retrobulbar space (behind theeye). Such a device has the major disadvantage of pressurizing the eye,the normal pressure of which is 18 mmHg. Above 21 mmHg, the risk ofacute glaucoma due to a sudden increase in ocular pressure is high, thisglaucoma leading to loss of vision on account of the optic nerve beingdamaged.

On the other hand, the use of this type of device causes pressure in theperiocular (retrobulbar and peribulbar) spaces. This pressure may leadto poor blood flow on account of compression at the head of the opticnerve. In some cases, this may go as far as venous or arterial occlusionleading to a partial or total loss of vision.

Another drawback due to such a device is that the wall of the ocularglobe is thick at this point. Moreover, this device does not make itpossible to precisely target the cells or the organs of the eye, and thesurface area treated is large. This does not make it possible to providecorrect and optimal treatment of an intraocular target that is to betreated, such as cells of the retina for example.

It is an object of the invention to provide a device for applying anactive principle by intraocular iontophoresis or electroporation whichmakes it possible to precisely target the zone that is to be treatedwhile avoiding the risk of glaucoma.

For this, there is provided according to the invention a device for theocular application of an active principle by peroperative intraoculariontophoresis or electroporation, comprising a reservoir that canreceive a solution comprising the active principle and diffusion meansfor diffusing the active principle, said diffusion means being connectedto the reservoir, the device also comprising injection means forinjecting the solution into the reservoir and means that can suck up thecontents of the reservoir during injection of the solution into thelatter by the injection means.

Thus, the presence of injection means (e.g., injection tube) coordinatedwith suction means (e.g., suction tube) makes it possible to maintain:

-   -   a constant and defined pressure within the reservoir,    -   a constant and defined volume if the reservoir can be deformed.

This is compatible with introducing the reservoir into the ocular globewithout substantially increasing the pressure of the globe. This avoidsthe risk of glaucoma and makes it possible to precisely approach thetarget cells that are to be treated and to treat only the latter,without there being any diffusion of active principle into the entireocular space.

Advantageously, the device has at least one of the followingcharacteristics:

-   -   the device comprises an injection tube and a suction tube which        extend inside one another and can be connected to the reservoir,    -   the diffusion means are arranged at a distal end of a probe,    -   the reservoir is arranged at the distal end,    -   the device comprises an injection tube and a suction tube which        extend into a probe,    -   the distal end of the probe forms an angle with respect to the        direction along which the probe mainly extends,    -   the angle is between 90° and 170°, thus allowing contact with        the retina while maintaining optimum visibility for manipulation        through the crystalline lens,    -   the angle is around 135°,    -   an iontophoresis or electroporation electrode extends in a        probe, in particular inside the reservoir,    -   the diffusion means comprise a porous wall that can allow the        active principle through, in particular under the effect of an        iontophoresis or electroporation current,    -   the reservoir has a wall that comprises at least one diffusion        orifice,    -   the orifice is covered with a permeable or semi-permeable        membrane that can allow the active principle through, in        particular under the effect of an iontophoresis or        electroporation current,    -   the lateral orifice is plugged on the reservoir side by a        stopper which is made of absorbent material that can allow the        active principle through, in particular under the effect of an        iontophoresis or electroporation current,    -   the device also comprises an optical fiber that can be connected        to a light source and arranged so as to illuminate the        environment of the diffusion means, in particular of the target        cells that are to be treated,    -   the device comprises a second optical fiber that can be        connected to a camera and arranged so as to record images of the        environment of the diffusion means, in particular of the target        cells that are to be treated.

There is also provided, according to the invention, a probe for theocular application of an active principle by intraocular iontophoresisor electroporation, comprising a reservoir that can receive a solutioncomprising the active principle and diffusion means for diffusing theactive principle, said diffusion means being connected to the reservoir,the probe also comprising an injection tube for injecting the solutioninto the reservoir and a suction tube for sucking up the contents of thereservoir.

There is also provided, according to the invention, a surgical methodthat can make use of the device having at least one of theaforementioned characteristics, which method comprises at least one ofthe following steps:

-   -   placement of a return electrode, which is connected to a        generator, onto the tissues neighboring the ocular globe that is        to be treated,    -   the return electrode is an electrode of the cutaneous type,    -   the return electrode can be positioned on all or part of the        external surface of the ocular globe,    -   incision of the sclera of the ocular globe that is to be        treated,    -   introduction, via the incision, of the probe into the vitreous        body,    -   positioning of the distal end of the probe in the vicinity of        the zone of the ocular globe that is to be treated,    -   injection into the reservoir, by the injection means, of a        solution comprising the active principle and regulation of the        pressure and/or volume of the reservoir by way of the suction        means,    -   charging of the electrode of the probe, which is connected to        the generator, for a given time and for a given voltage,    -   stopping of the generator,    -   withdrawal of the probe and of the return electrode,    -   closing of the incision in the sclera.

Other characteristics and advantages of the invention will becomeapparent from the following description of a preferred embodiment and ofvariants. In the attached drawings:

FIG. 1 is a schematic representation of an intraocular applicationdevice according to the invention,

FIG. 2 a is a partial view of the distal end of a probe according to afirst embodiment of the invention,

FIG. 2 b is a section on IIb-IIb of the distal end of the probe of FIG.2 a,

FIG. 3 a is a partial view of the distal end of the probe according to asecond embodiment of the invention,

FIG. 3 b is a view in section on IIIb-IIIb of the distal end of theprobe of FIG. 3 a,

FIG. 4 is a view in section of the distal end of a probe according to athird embodiment of the invention,

FIGS. 5 a to 5 e are different embodiments of the distal end and of thereservoir of a probe according to the invention,

FIG. 6 shows a probe according to a variant embodiment of the invention,

FIG. 7 is an anatomical section of an ocular globe, and

FIG. 8 is an anatomical section of the ocular globe showing theinsertion during use of a probe according to the invention.

With reference to FIG. 1, a description will be given of a device forthe ocular application of an active principle by intraoculariontophoresis or electroporation according to the invention. The device1 comprises a current generator 2 which is connected to a firstelectrode 3, known as the return electrode, and to a second electrode 8,known as the main electrode or active electrode. A reservoir 7 isassociated with this main electrode 8, which reservoir can receive theactive principle that is to be applied or else a solution comprising theactive principle. The reservoir 7 comprises injection means 4 andsuction means 5. Moreover, the reservoir comprises a porous wall 6 thatcan allow the active principle through only during iontophoresis orelectroporation. The reservoir 7 may be mounted on a probe 9.Preferably, the reservoir is situated at the distal end of the probe 9.

The return electrode 3 is designed to close the electrical circuitformed by the generator, the main electrode and the organic tissues. Theelectrode 3 is placed opposite the main electrode 8 and the organictissues that are to be treated or else preferably in the near vicinityof these tissues that are to be treated, as will be seen below. In thiscase, the return electrode 3 is a cutaneous electrode of the TENS type(Transcutaneous Electrical Nerve Stimulation). It is mainly composed ofa conductive skin adhesive and of a conductive carbon film that isconnected to the generator by an electrical wire.

The main electrode 8 is preferably made of a material chosen from a widerange of electrically conductive materials. These materials may be:

-   -   inert. They do not corrode electrochemically on account of the        presence of the electric current during operation of the device.        These inert materials are stainless steel, platinum, gold,        carbon, tungsten, etc.    -   sacrificial. They are converted, under the action of the        electric current during operation of the device, into metal ions        which precipitate, avoiding electrolysis of the solution        comprising the active principle. These materials are silver,        copper, etc.

According to other variant embodiments, the main electrode 8 consists ofink or of conductive polymer, or else of conductive particles dispersedin a matrix.

Moreover, the main electrode 8 is in the form of a wire, a film, a plateor even a woven material.

The current generator 2 supplies a DC current having an intensity ofbetween about 0.5 and 5 mA, for a period ranging from about 0.5 to 10minutes. Depending on the resistance of the organic tissues involved inthe circuit, which resistance may vary during iontophoresis, the currentsupplied by the generator 2 adapts according to Ohm's law U=R.I, where Uis the current in Volts, R is the resistance in Ohms and I is theintensity in Amps; however, the current supplied by the generator 2 cannever exceed 20 V.

According to one variant embodiment, the generator 2 may be an ACcurrent generator. The AC current has the advantage of avoidingvariation of the pH on account of oxidoreduction phenomena at the mainelectrode. The frequency range of this AC current is chosen so as toallow optimal permeability of the tissues that are to be treated. Inthis case, the return electrode 3 is preferably an electrode of the ECGtype (ElectroCardioGram) and is composed of a skin adhesive and of anAg/AgCl film having a very low impedance.

According to another variant embodiment, the generator 2 may supply acurrent profile having voltage peaks which are very high between about50 and 2500 V, and of very short duration, between about 0.01 and 0.1 s,at a very low intensity. This type of profile is usually used inelectroporation.

The probe 9 comprises, in this case, three main parts: a connectionsocket 13, a tube 12 and a distal end 7 comprising the reservoir 7. Theconnection socket 13 is of the female Luer type which is the universalstandard for connection of intravenous catheters. This socket has thegeneral shape of a cone having an inlet diameter of around 4 mm and aconicity of around 6%. The tube of the probe is made of a biocompatiblepolymer material, preferably such as polyvinyl chloride, polyethylene,polypropylene, polyamide, polyether block amide, polyurethane orsilicone, depending on the desired hardness and transparencycharacteristics.

With reference to FIGS. 2 a and 2 b, a description will be given of afirst embodiment of the probe 9. The probe 9 comprises an injection tube4 that opens into the reservoir 7 located at the distal end of the probe9. This tube 4 travels along the probe 9 essentially parallel to alongitudinal axis of said probe. Likewise, a suction tube 5 travelsessentially parallel to the tube 4 within the probe 9 and plunges intothe reservoir 7. As shown in FIG. 2 b, the probe is preferably ofcircular cross section, as are the tubes 4 and 5. The diameter of thiscircular cross section is between about 0.9 mm (gauge 20) and about 2.1mm (gauge 14). The length of the probe 9 is between about 20 and 50 mm.

With reference to FIGS. 3 a and 3 b, a description will be given of asecond embodiment of the probe 9. The probe 9, as above, has aninjection tube 4 that opens into the reservoir 7 located at the distalend of the probe. The tube 4 has a longitudinal axis that is almostcoincident with a longitudinal axis of the probe 9. The latter acts as asuction tube 5. The electrode 8 is located essentially along thelongitudinal axis of the tube 4 and of the probe 9. The probe 9 and thetube 4 preferably have a circular cross section. The electrode 8, theinjection tube 4 and the probe 9 are thus essentially coaxial.

With reference to FIG. 4, a description will be given of a thirdembodiment of the probe 9. As shown in this figure, the probe 9 has acircular cross section. Within this probe 9 there travel, in a manneressentially parallel to a longitudinal axis of the probe 9, an injectiontube 4 of preferably circular cross section and a suction tube 5 ofpreferably circular cross section, in which the electrode 8 is located.Moreover, the probe 9 has a first optical fiber 10 which is connected toa light source (not shown) so as to guide light rays into the vicinityof the distal end of the probe 9 to illuminate the environment of thetarget that is to be treated. Finally, the probe 9 may have a secondoptical fiber 11 which is connected to a camera and can guide towardthis camera light rays coming from the distal end of the probe so as tomake the camera record images of the environment of the target that isto be treated. The presence of these optical fibers makes it possible toimprove the precision with which the probe will be manipulated to treatthe target by iontophoresis or electroporation.

With reference to FIGS. 5 a to 5 e, a description will be given ofdifferent embodiments of the wall of the reservoir.

With reference to FIG. 5 a, the wall 106 of the reservoir 7 has amultitude of micro-orifices 107 passing through the wall 106. Thesemicro-orifices 107 can allow the molecules of the active principlethrough, under the action of the electric field emitted by the electrode8, which makes it possible to carry out iontophoresis orelectroporation. Preferably, the various micro-orifices 107 areuniformly distributed over a strip surrounding the reservoir, the widthof which strip does not exceed the size of the reservoir. Morepreferably, various micro-orifices are located on a limited portion ofthe wall of the reservoir. The micro-orifices have a mean diameter ofbetween about 0.01 and 0.1 mm.

With reference to FIG. 5 b, the probe 9 is open at its distal end 9 anda balloon 206 is slipped over the open distal end of the probe 9, theballoon acting as reservoir 7. The membrane forming the balloon 206 is apreferably semi-permeable or permeable or even micro-porous membranethat can allow the molecules of the active principle through only underthe action of the electric field generated by the electrode 8 duringiontophoresis or electroporation.

In FIG. 5 c, the distal end of the probe 9 has a porous end-piece 306surrounding the reservoir 7. The porous end-piece can allow themolecules of the active principle through only under the effect of theelectric field generated by the electrode 8 during iontophoresis orelectroporation.

In FIG. 5 d, the distal end of the probe 9 has an orifice 406 that canallow the reservoir 7 to communicate with the exterior of the probe.Preferably, the orifice 406 is located on a lateral wall surrounding thereservoir 7. This orifice 406 is plugged by a preferably permeable orsemi-permeable or even micro-porous membrane 407. This membrane 407 maybe located on the orifice 406 inside the reservoir 7 or else positionedon the orifice 406 outside the reservoir 7. Preferably in this case, themembrane may be a sleeve that is slipped over the distal end of theprobe and covers the orifice 406. The through-orifice is made by apiercing with a mean diameter of between about 0.5 and 1 mm. Themembrane has a porosity of between about 1 and 10 μm.

In FIG. 5 e, the end of the probe 9 has the same end configuration asthat shown in FIG. 5 d. In this case, the orifice 406 is plugged by anabsorbent material 507 which takes up the majority of space in thereservoir 7. The absorbent material 507, like the membrane 407, canallow the molecules of the active principle through only under theeffect of an electric field coming from the electrode 8 duringiontophoresis or electroporation. The absorbent material is preferablyfoam or sponge.

In all the embodiments of the probe 9 described above, the mainelectrode 8 must be placed opposite either the membrane or the orificesso as to allow an optimal flow of the electric current to the outside ofthe probe 9 during operation.

Moreover, according to the embodiments described above, the effectivetreatment surface area of target cells is between about 50 μm indiameter and about 2 mm in diameter.

With reference to FIG. 6, the probe may be bent at its distal end. Theangle α that the distal end forms with the tube 12 of the probe may bebetween 90° and 170°. Preferably, this angle is more or less equal to135°. The choice of this angle of 135° depends on the route used tointroduce the probe into the ocular globe, as will be seen below. Theangle is chosen so that the longitudinal axis of the distal end of theprobe 9 is essentially parallel to the surface formed by the targetcells that are to be treated. In one variant embodiment (not shown), theangle that the distal end of the probe forms with the tube of the probeis chosen by the operator during the surgical procedure, so as toperfect the previous alignment. For this, the distal end of the probe 9comprising the reservoir 7 is mounted to rotate, about an axis (notshown) that is perpendicular to the axis along which the probe mainlyextends, on the tube of the probe 9, and the application devicecomprises means for using this end that are located at the proximal endof said probe.

A description will now be given of the use in practice of the device forapplication by intraocular iontophoresis or electroporation according tothe invention.

With reference to FIG. 7, the eye 600 has the overall shape of aballoon. The anterior part of the wall consists of a transparent cornea608 behind which there is a pupil 607. The latter is separated from thecornea 608 by an anterior chamber 605 comprising an aqueous humor. Thepupil is closed by a transparent crystalline lens 604 which is shaped inthe manner of a convergent lens. The volume 606 located behind thecrystalline lens 604 is called the vitreous body. The posterior wall ofthe eye consists of a first layer 601 which forms the functional retina,then of a second layer 602 called the choroid and then finally of athird layer 613 called the sclera. At the rear end of the ocular globethere is an optic nerve 603. The crystalline lens 604 is kept at thefront by an iris 609 and is connected to the wall of the ocular globe atthe limit between the cornea and the sclera by a ciliary body 611.Between the point of attachment of the ciliary body 611 and the start ofthe functional retina 601 there is a non-functional pars plana 615. Froma limb 610 surrounding the cornea 608, there is a layer of tissue 612,known as conjunctive tissue, extending above the sclera up to the pointof implantation of the eyelids 614.

With reference to FIG. 8, a description will be given of the mode ofoperation. The surgeon undertakes a transcleral route by making anincision in the sclera at the non-functional pars plana 615. This isbecause the wall forming the ocular globe is least thick at thisparticular point. Next, the surgeon positions the electrode 3 of theapplication device 1 on the skin of the face as close as possible to theeye, preferably on the forehead, the cheek or the eyelid (it is alsopossible to position the return electrode under the conjunctive tissue,in direct contact with the ocular globe, or even directly into the eye).Next, he introduces, via the incision made in the sclera, the probe 9which then penetrates into the vitreous body 606. The surgeon, has thepossibility of monitoring the introduction of the probe either directlythrough the cornea and the crystalline lens, which are transparent, orelse with the aid of a camera if the probe is equipped with an opticalfiber for this purpose, or else with the aid of a slot lamp or a lens.The introduction of the probe 9 is carried out such that the curveddistal end 7 comes into the vicinity of the cells that are to betreated. Once the probe 9 has been put in place, the surgeon makes acurrent flow into the electrode 8 so as to carry out iontophoresis orelectroporation, during which a certain amount of active principle,depending on the intensity of the current on the one hand and the timefor which current is supplied on the other, is transferred from thereservoir 7 into the target cells that are to be treated. Next, thesurgeon withdraws the probe 9 and then closes his incision.

As has been seen, the configuration of the probe 9 and the route usedmake it possible to apply the active principle in a very localizedmanner, without affecting the tissues that are not to be treated.

The main indication for the use of the application device 1 is retinalvessel occlusion, a classic cause of total or partial loss of vision,particularly in elderly people. It is also one of the complications ofdiabetic retinopathies.

There are two forms of retinal vessel occlusion:

-   -   the ischemic form, which is the rarest (10% to 15% of cases), is        manifested by a sharp drop in visual sharpness, evolving toward        neovascularization and glaucoma,    -   the edematous form, which is the most frequent (60% to 80% of        cases), is manifested by a visual haze, and evolves either        toward remission in the case of young patients or toward a        chronic form with slow degradation of the retina or finally        toward the ischemic form described above.

Vessel occlusion is considered an emergency and is currently treated byfibrinolytic treatments (thrombolysis or dissolution of the clots) bythe general or local route, or by rheological treatments (removal of acertain amount of blood) by the general route, or else by laserphotocoagulation treatments which make it possible to prevent or regressneovascularization on the one hand and to combat macular edema on theother. The case of injecting fibrinolytics by the general route presentssignificant hemorrhagic complications. In the case of injecting thesesame fibrinolytics by the local route (that is to say via the vitreousbody), the occurrence of intraocular hemorrhages is observed. Thus, thedevice for application by iontophoresis or electroporation 1 accordingto the invention allows the injection of these same fibrinolytics ontothe sole target tissue that is to be treated, while avoiding thehemorrhagic complications described above.

Other ocular pathologies may be treated by a device for application byiontophoresis or electroporation according to the invention. Theseinclude degenerative diseases of the retina that are linked with age andalso diabetic retinopathies in general. Many molecules are beingdeveloped to slow down or even halt the neovascularization observed inthese pathologies. These molecules may be injected using a deviceaccording to the invention. This makes it possible to increase the localconcentrations of these medicaments on the one hand and on the otherhand to be able to pass larger molecules into the target tissues, suchas for example during a localized administration of antimitotics or ofantiangiogenics.

Likewise, the device according to the invention may be used for thetransfection by iontophoresis or electroporation of plasmids or ofmedicaments for gene therapy (such as for example of chimeric orantisense oligonucleotides, or else ribozymes), the main mode of actionof which is to correct genes or fragments of genes inside the targetcells.

Of course, many modifications may be made to the invention withoutthereby departing from the scope thereof.

1. A device for an ocular application of an active principle byperoperative intraocular iontophoresis or electroporation within anocular globe of an eye, comprising: a reservoir arranged for being atleast partly introduced into the ocular globe, close to cells to betreated, the reservoir receiving a solution comprising the activeprinciple; means for injecting the solution into the reservoir; meansfor sucking up contents of the reservoir during injection of thesolution into the reservoir by the injection; and a porous reservoirwall of the reservoir, the porous reservoir wall being folly introducedinto the ocular globe, at least a portion of which is configured toprovide porous access to the reservoir, the porous access configured toallow molecules of the active principle to pass through the porousreservoir wall only under the effect of an electric field.
 2. The deviceas claimed in claim 1, wherein the means for injecting comprising aninjection tube and the means for sucking comprising a suction tube, theinjection tube and the suction tube extend inside one another and can beconnected to the reservoir.
 3. The device as claimed in claim 1, whereinthe reservoir is arranged at a distal end of a probe.
 4. The device asclaimed in claim 3, wherein the distal end of the probe forms an angle(α) with respect to the direction along with the probe mainly extends.5. The device as claimed in claim 4, wherein the angle is between 90°and 170°.
 6. The device as claimed in claim 5, wherein the angle isaround 135°.
 7. The device as claimed in claim 3, wherein the porousreservoir wall includes a porous end-piece positioned at a distal end ofthe probe surrounding the reservoir.
 8. The device as claimed in claim1, comprising an injection tube and a suction tube which extend into aprobe.
 9. The device as claimed in claim 1, wherein an iontophoresis orelectroporation electrode extends in a probe, the reservoir beingarranged at a distal end of the probe.
 10. The device as claimed inclaim 1, wherein the porous reservoir wall comprises a plurality ofmicro-orifices passing through the wall.
 11. The device as claimed inclaim 1, wherein at least a portion of the porous reservoir wallcomprises a balloon having a semi-permeable membrane.
 12. The device asclaimed in claim 1, wherein the porous reservoir wall defines anorifice, the device including a porous membrane positioned to plug theorifice and provide porous access to the reservoir.
 13. The device asclaimed in claim 1, further comprising an optical fiber that can beconnected to a light source and arranged so as to illuminate theenvironment of the diffusion means, in particular of the target cellsthat are to be treated.
 14. The device as claimed in claim 13,comprising second optical fiber that can be connected to a camera andarranged so as to record images of the environment of the diffusionmeans, in particular of the target cells that are to be treated.
 15. Thedevice as claimed in claim 1, wherein the porous reservoir wall definesan orifice, the device including an absorbent material positioned toplug the orifice and provide porous access to the reservoir.
 16. Thedevice as claimed in claim 1, wherein the at least a portion of theporous reservoir wall providing porous access comprises a one or moremicro-orifices having a mean diameter of between about 1 μm and about 10μm.
 17. A probe for an ocular application of an active principle byintraocular iontophoresis or electroporation within an ocular globe ofan eye, comprising: a reservoir arranged for being at least partlyintroduced into the ocular globe, close to cells to be treated, thereservoir receiving a solution comprising the active principle; aninjection tube for injecting the solution into the reservoir; a suctiontube for sucking up the contents of the reservoir; and a porousreservoir wall of the reservoir, the porous reservoir wall being fullyintroduced into the ocular globe, at least a portion of which isconfigured to provide porous access to the reservoir, the porous accessconfigured to allow molecules of the active principle to pass throughthe porous reservoir wall only under the effect of an electric field.18. The device as claimed in claim 17, wherein the at least a portion ofthe porous reservoir wall providing porous access comprises a one ormore micro-orifices having a mean diameter of between about 1 μm andabout 10 μm.
 19. The device as claimed in claim 17, wherein the porousreservoir wall comprises a plurality of micro-orifices passing thoughthe wall.
 20. The device as claimed in claim 19, wherein themicro-orifices have a mean diameter of between about 0.01 mm and 0.1 mm.21. A device for an ocular application of an active principle byperoperative intraocular iontophoresis or electroporation, comprising: aprobe having proximal end and a distal end, comprising: a reservoir atthe distal end for receiving a solution comprising the active principle;at least two fluid channels in fluid communication with the reservoir;and an electrode disposed with the probe configured to create anelectric field for applying the active principles to an ocular componentof an eye; at least one of the fluid channels configured to deliver theactive principles to the reservoir; and at least another fluid channelconfigured to remove contents from the reservoir during the delivery ofthe active principles.